Currently, more than 1,200,000 people in the United States are colorectal cancer (CRC) survivors; each year, 140,000 more Americans are diagnosed with the disease. Finding cost-effective ways to prevent CRC recurrence is therefore an important public health goal. The long-term objective of our research is to improve the health of cancer survivors in the real world, where people have chronic conditions for which they take prescription and over-the-counter medications. Our objective aligns with the National Cancer Institute's Annual Plan and Budget Proposal for Fiscal Year 2012, which highlights the importance of research on multiple chronic conditions in cancer patients. With a median age at diagnosis of 70 years, CRC tends to occur in an age group burdened with comorbidities. Medications for these conditions are linked to CRC risk in laboratory, animal, and epidemiologic studies. However, surprisingly little is known about how medications commonly used to treat prevalent chronic conditions, such as diabetes and hypertension, affect CRC recurrence risk. Therefore, we seek to evaluate the influence of commonly used medications on CRC recurrence. Our hypothesis is that medications are modifiable risk factors, with some showing promise as chemo preventive agents and some associated with an increased risk of recurrence in CRC survivors. We will test our hypotheses through a retrospective population-based cohort study in two integrated healthcare delivery systems. We will identify approximately 3300 incident stage I-IIIA colorectal cancers diagnosed from 1995- 2014. Cancer recurrence-which is not documented in tumor registries-will be ascertained from targeted medical chart review. By relying on a database of all dispensed medications and reviewing medical charts for over-the-counter medications, the study will avoid selection and recall bias. High-quality information on factors that might confound analyses will be efficiently collected from targeted chart review, complete automated health plan data, and surveys of recently diagnosed patients. A variety of well-established methods will be used to control for confounding in survival analysis to produce estimates of the relative risk of recurrence associated with common medications. Secondary analyses will focus on disease-free survival and all-cause mortality. The results from this clinically relevant, high-impact study will help CRC survivors and their providers make evidence-based decisions about how to manage chronic conditions.